That breast cancer may aggregate in families has been amply demonstrated during the past half century. A family history of the disease is also a well-accepted risk factor, capable of increasing the risk two- to three-fold in first-degree relatives of patients compared with control relatives. Not so well-accepted, however, is the etiological basis of familial aggregation. Because of the frequency of breast cancer in the population some contend that familial aggregation is a chance phenomenon. Others ascribe it to the inheritance of genetic factors and still others to the transmission of cultural practices. The aim of the present proposal is to determine whether familial aggregation in an unselected series of families is best explained by the transmission of a major gene, a transmissible multifactorial component acting alone or in concert with a major gene, or by an independent environmental contribution. Segregation analysis under a mixed model will be applied to three data sets: the families of 267 unselected female breast cancer patients, the families of 133 consecutive breast cancer patients with bilateral disease, and the families of 133 unselected male breast cancer patients. This represents the first application of segregation analysis to a large series of unselected pedigrees from the United States and the first application to families of male and bilateral patients. Little is known about the familiality of male breast cancer. Although it is rare, there is evidence to suggest that males with breast cancer have inherited a high liability to the disease; if so, then their female relatives would be expected to represent a genetically high-risk group. The relatives of bilateral patients may be similar in this regard. The use of three independent data sets will increase the power to resolve the question of the cause(s) underlying the familial aggregation of breast cancer, and whether the cause(s) are the same or different in the three familial groups. The analysis will also generate empiric and analytic recurrence risks. The project will thus have practical relevance to genetic counseling and early detection, as well as providing insight into the mechanisms underlying familial breast cancer.